Quinidine reactions

Detection. Cinchonidine is distinguished from quinine and quinidine by not being fluorescent in dilute sulphuric acid, and by not giving the thalleioquin reaction and from cinchonine in being laevorotatory and more soluble in ether, and in the sparing solubility of its tartrate. 

In the cases of quinine and quinidine there is an additional complication, except for reaction (c), owing to partial de-methylation of the methoxyl group, thus in the action of sulphuric acid on quinine there may be four products of formula E, viz., the two geometrical isomerides apoquinine and isoapoquinine (for which Q is 6-hydroxyquinolyl) and their methyl ethers, j8-isoquinine and a-isoquinine respectively (for which Q is 6-methoxyquinolyl). 

The results of this additional compliqfition may be illustrated by a comparison of the reaction products in the cases of cinchonine and quinidine. 

The pH of the reaction mixture is taken both before and after the addition of the last portion of the quinidine-methanol solution. The mixture is gently warmed (30° to 50°C), and the pH determined at 20 minute intervals. At the end of 4 hours, or when the reaction has gone to completion as evidenced by the pH of the mixture (between pH 6.5 and 7.5), the stirring is then stopped and the mixture cooled to 0°C and filtered. The solvent is evaporated to dryness under reduced pressure, utilizing as little heat as is feasible. The dried residue Is powdered and suspended in 10 volumes of methanol and filtered. The insoluble powder is dried, and is quinidine polygalacturonate, melting at 180°C with decomposition. 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Mr. Parker is at an outpatient clinic for a follow-up visit. He has been taking quinidine for several months for a cardiac arrhythmia. Analyze what assessments you would make on Mr. Parker to determine the effectiveness of quinidine therapy. Discuss what questions you would adz to determine the presence of any adverse reactions. 

The thalleiochin reaction for the specific detection of quinine alkaloids carrying an oxygen group at C-6 of the quinoline nucleus (e. g. quinine and quinidine) [17], or the... 

Azirines can be prepared in optically enriched form by the asymmetric Neber reaction mediated by Cinchona alkaloids. Thus, ketoxime tosylates 173, derived from 3-oxocarhoxylic esters, are converted to the azirine carboxylic esters 174 in the presence of a large excess of potassium carbonate and a catalytic amount of quinidine. The asymmetric bias is believed to be conferred on the substrate by strong hydrogen bonding via the catalyst hydroxyl group <96JA8491>. 

Interestingly, certain chiral tertiary bases, viz., the Cinchona alkaloids, result in an asymmetric 1,3-elimination to give enantiomerically enriched azirine esters 29 (Scheme 15). The best results were obtained with quinidine in toluene as the solvent at a rather high dilution (2 mg mL ) at 0 °C. In an alcoholic solvent no asymmetric conversion was observed. It is of importance to note that the pseudoenantiomers of the alkaloid bases gave opposite antipodes of the azirine ester, whereby quinidine leads to the predominant formation of the (k)-enan-tiomer (ee = -80%). To explain this asymmetric Neber reaction, it is suggested... 

The answer is a. (Katzung, p 162.) Many drugs can cause an immunohemolytic anemia. Methyldopa may cause a positive Coombs test in as many as 20% of patients, along with hemolytic anemia. Other drugs with similar actions on red blood cells are penicillins, quinidine, procainamide, and sulfonamides. These form a stable or unstable hapten on the red cell surface, which induces an immune reaction I immunoglobulin G (IgG) antibodies] and leads to dissolution of the membrane. 

The answer is b. (Hardmanr p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I bio transformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

Further evidence for the formation of intermediate compounds in catalytic reactions is afforded by the observation (a) that optically active camphor is formed from optically inactive (racemic) camphor carboxylic acid in the presence of the d- or /-forms of quinine, quinidine or nicotine and (6) that optically active bases, e.g., quinidine, catalyze the synthesis of optically active mandelonitrile from benzaldehyde and hydrocyanic acid.10 These results hardly admit of any other interpretation than the intermittent production of a catalyst-reactant compound. 

The structures of quinine, cinchonidine, quinidine, and cinchonine are shown in Figure 3. Other workers (16,17) have discussed these alkaloids and their use as catalysts in some detail. An excellent discussion of cinchona-alkaloid-catalyzed reactions prior to 1968 was given by Pracejus (18). In this section we discuss only four aspects of these reactions. 

Quinine and quinidine, as well as cinchonidine and cinchonine, are diastereo-meric pairs. However, at the critical sites—the P-hydroxyamine portions of the molecules—they are enantiomeric. Thus if quinine is used as the chiral catalyst in an asymmetric transformation (i.e., with one enantiomer being formed in excess), the other enantiomer is formed in excess when quinidine is used. Table 2 gives a representative example, the thiol addition reaction (19). 

These reactions, performed many times, show, in addition to the reversal of the absolute configuration of the product with the change in the configuration at C-8 and C-9 of the alkaloids, a small but reproducible difference in the e.e. of the product. It is evident that the diastereomeric nature of quinine vs. quinidine and cinchonidine vs. cinchonine expresses itself via small but important energy differences in the best fits of the transition states. Noteworthy in this respect is the fine work of Kobayashi (20), who observed larger differences (in the e.e. s of products) when the diastereomeric cinchona alkaloids were used as catalysts after having been copolymerized with acrylonitrile (presumably via the vinyl side chain of the alkaloids). 

We have studied this reaction in considerable detail (88) and have found that when one uses quinine (eq. [25]) or any one of the chiral bases, a variety of aldehydes react with ketene to form the corresponding p-lactones in excellent chemical and nearly quantitative enantiomeric yields. Equation [25] exemplifies the reaction. Note that mild basic hydrolysis of the lactone furnishes a trichlo-rohydroxy acid that was prepared earlier by McKenzie (89). If one uses quinidine as catalyst, the process furnishes the natural (S)-malic acid. Note that ketene first acylates the free hydroxyl group of quinine, so that the actual catalyst is the alkaloid ester. 

The cycloaddition of aldehydes and ketones with ketene under the influence of quinine or quinidine produce chiral 2-oxetanones [46,47]. Solvolytic cleavage of the oxetanone, derived from chloral, and further solvolysis of the trichloromethyl group leads to (5)- and (R)-malic acids with a 98% ee [46] (the chirality of the product depends on the configuration of the catalyst at C-8 and, unlike other alkaloid-induced reactions, it is apparently independent of the presence of the hydroxyl group). No attempts have been made to catalyse the reaction with chiral ammonium salts. 

Sharpless stoichiometric asymmetric dihydroxylation of alkenes (AD) was converted into a catalytic reaction several years later when it was combined with the procedure of Upjohn involving reoxidation of the metal catalyst with the use of N-oxides [24] (N-methylmorpholine N-oxide). Reported turnover numbers were in the order of 200 (but can be raised to 50,000) and the e.e. for /rara-stilbene exceeded 95% (after isolation 88%). When dihydriquinidine (vide infra) was used the opposite enantiomer was obtained, again showing that quinine and quinidine react like a pair of enantiomers, rather than diastereomers. 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

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